A tissue test to improve the identification of men at risk for undetected clinically significant prostate cancer

“Rule-in” high-risk men who have had a previous negative biopsy result, may be harboring undetected cancer (a false-negative biopsy result), and therefore may benefit from a repeat biopsy and appropriate treatment.

The Most Significant Predictor of Prostate Cancer Detection on Repeat Biopsy

Independently published clinical studies have shown that for men who have received a negative prostate biopsy result, ConfirmMDx is the single most significant predictor of patient outcome among all currently available clinical factors, such as age, PSA level, and DRE results.1,2

ConfirmMDx Improves Upon the Current Standard of Care

Under the current standard of care:

Men with an elevated or rising PSA level (≥ 4.0 ng/ml) and/or abnormal digital rectal exam (DRE) are considered at high risk for cancer and often are referred for a prostate biopsy to determine if prostate cancer is present.

The standard prostate biopsy procedure takes 10-12 core samples, and histopathological review by visual inspection under a microscope remains the gold standard for the diagnosis of prostate cancer.

This schema, however, samples less than 1% of the entire prostate gland and results in limited histopathological analysis.

Sampling error is an inherent and well-documented issue, with false-negative rates of prostate biopsy procedures reported as high as 25-35%.3,11

Of an estimated 500,000 biopsies performed each year, less than one-third actually result in a cancer finding, leaving more than 300,000 men with a negative biopsy reading but still facing elevated clinical risk factors.3,11,12 Concerns over inconclusive (false-negative) biopsy results, coupled with the high rate of clinically significant cancer detected upon repeat biopsy, pose a diagnostic dilemma:

43% of patients with negative histopathology on initial biopsy will undergo a repeat biopsy, many also continuing on to 3rd and 4th biopsies.

Repeat biopsies are invasive procedures resulting in increased risk of infection and hospitalization.

Significant costs are associated with unnecessary procedures and associated risks.13,15

For patients with a negative biopsy but with persistently elevated or rising PSA, abnormal DRE, or other risk factors, few options are currently available to guide a urologist in determining the patients need for an additional biopsy procedure is warranted. Fear of undetected prostate cancer leads to additional procedures, with many men being subjected to repeated invasive biopsies to rule-out the presence of cancer.

ConfirmMDx is a Well-Validated Epigenetic Test that Guides the Detection of Occult Prostate Cancer on a Patient’s Previously Biopsied Negative Tissue

The use of ConfirmMDx for prostate cancer detection using methylation-specific PCR (MSP) and cancer-associated epigenetic biomarkers to improve upon histopathology has been well validated in both scientific and clinical studies.

DNA methylation, the most common and useful measure of epigenetic abnormality testing, is responsible for the silencing of key tumor suppressor genes. DNA methylation biomarkers associated with prostate cancer have been extensively evaluated. More than 55 studies on the ConfirmMDx genes and technology have been published in peer-reviewed, scientific and medical journals.

GSTP1 is the most intensely studied and widely reported epigenetic biomarker associated with prostate cancer diagnosis, encoding the glutathione S-transferase Pi 1 protein involved in detoxification, due to its high sensitivity and specificity.1,2,11

Complementing GSTP1, methylation of the APC and RASSF1 genes is frequently found in prostate cancer, and these markers have demonstrated a “field effect” aiding in the identification of biopsies with false-negative histopathological results.1,2,11

The concept of a field cancerization effect, when first reported in medical literature by Slaughter in 1953, described the changes in tissues surrounding cancer lesions and their association with development of tumors. Later, the term “field effect” evolved to include molecular changes in adjacent, benign-looking tissues. The epigenetic field effect is a molecular mechanism whereby cells adjacent to cancer foci can contain DNA methylation changes, which may be indistinguishable by histopathology, but detectable by MSP testing. The presence of epigenetic field effects associated with prostate cancer has been widely published and is the basis of activity for the ConfirmMDx assay to aid in the detection of occult prostate cancer on previously biopsied, histopathologically negative tissue.15-22

Over 55+ Published Studies on the Test, Genes and Technology

Clinical Validation

Study of 211 African American Men

The study participants from 7 urology centers across the US were all undergoing 12-core trans-rectal ultrasound-guided repeat biopsy within 30 months from a negative index biopsy. All biopsy cores from the negative index biopsy were profiled for the epigenetic biomarkers GSTP1, APC, and RASSF1 using ConfirmMDx for Prostate Cancer. In this group of African American men, ConfirmMDx’s accuracy for predicting repeat biopsy outcomes was equivalent to prior studies conducted in predominantly Caucasian populations.

96% Negative Predictive Value for High-grade Cancer

The study included 803 men with two consecutive biopsies within 24-30 months.

Low DNA-methylation levels in PCa-negative biopsies led to an NPV of 96% for high-grade cancer.

The ConfirmMDx risk score, comprising DNA-methylation intensity and traditional clinical risk factors, improved the identification of men with high-grade cancer, with a maximum avoidance of unnecessary repeat biopsies. This risk score resulted in better patient risk stratification and significantly outperformed current risk prediction models such as PCPTRC and PSA.

The DOCUMENT Study: The Most Significant, Independent Predictor for Prostate Cancer in a Repeat Biopsy

The study demonstrated that the ConfirmMDx for Prostate Cancer test is the most significant, independent predictor for prostate cancer detection in a repeat biopsy in a cohort of U.S. men.

The findings are consistent with and confirm the results of the earlier European MATLOC study. This blinded, multicenter, confirmatory clinical validation study on 350 PSA-screened men used the same assay cutoffs applied in the MATLOC study and verified the test’s high negative predictive value. The study was led by principle investigator Alan Partin, MD, PhD, Professor and Chief of Urology at the James Buchanan Brady Urological Institute at Johns Hopkins School of Medicine.

The MATLOC Study Included 483 Men with an Initial Negative Biopsy, Followed by a Positive or Negative Repeat Biopsy within 30 Months

This study demonstrated that ConfirmMDx for Prostate Cancer improved on histopathology alone, by accurately identifying two-thirds of the prostate cancer patients missed in the previous biopsy and correctly identifying approximately two-thirds of the men who could forego a repeat biopsy.

ConfirmMDx yielded sensitivity of 68%, specificity of 64%, and a NPV of 90% to confirm the absence of cancer in histopathologically negative biopsy cores. This represents a significant improvement over histopathology alone, which yields a NPV of 65% to 75%.

Clinical Utility

Reduced Rate of Repeated Prostate Biopsies Observed in ConfirmMDx

A total of 5 clinical urology practices that had ordered a minimum of 40 ConfirmMDx tests for patients with previous, cancer-negative biopsies over the course of 18 months participated in the study.

A total of 138 patients who were considered at risk for malignancy based on traditional risk factors, but had ConfirmMDx negative test results, were identified and all were included in the analysis. A very low rate of repeat biopsies (4.4%) was observed in the ConfirmMDx negative men, as compared to the 43% rate of repeat biopsy reported in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, a large population-based randomized trial designed and sponsored by the National Cancer Institute. Repeat biopsies had been performed in 6 of the 138 (4.3%) men with a negative assay result, in whom no evidence of cancer was found on histopathology. These positive clinical utility results, which demonstrated a 10-fold reduction in the rate of repeat biopsy as compared to the reported standard of care, served as the basis for ConfirmMDx’s Medicare coverage.

In a budget impact model (BIM) developed to evaluate the effect of the ConfirmMDx assay on healthcare spending, the model demonstrates the potential healthcare savings associated with the reduction of repeat biopsies and complications avoided. The BIM compares a standard of care scenario, based upon up-to-date prostate cancer biopsy statistics, procedures, and Medicare fee schedules, to a new scenario wherein the ConfirmMDx assay is employed for decisions on repeat biopsy.

The model shows that the net cost to a commercial health plan with 1 million members would be reduced by approximately $500,000 if patients with histopathologically negative biopsies were managed with the use of the epigenetic assay to differentiate patients who should undergo repeated biopsy and those who should not. Using this genetic-based assay can save costs to health plans and to the US healthcare system and improve the clinical man¬agement of patients with elevated PSA levels.

Analytical Validation

This MDxHealth validation study describes the successful development of the ConfirmMDx multiplex DNA methylation test. In the same study, the effect of prostate needle core biopsy sample volume and age of formalin-fixed paraffin-embedded (FFPE) samples were evaluated. ConfirmMDx can be applied to small biopsy specimens widening clinical applicability, and the age of the FFPE-samples does not have a negative impact on the performance of the test.

Kronz JD et al.: Predicting cancer following a diagnosis of high-¬‐grade prostatic intraepithelial neoplasia on needle biopsy: data on men with more than one follow-¬‐up biopsy. American Journal of Surgical Pathology 2001; Aug 25(8): 1079–1085.

Based on MDxHealth management estimates taken from publicly available Medicare and other data.

Trock BJ et al.: Evaluation of GSTP1 and APC Methylation as Indicators for Repeat Biopsy in a High-risk Cohort of Men with Negative Initial Prostate Biopsies. British Journal of Urology International 2012; July 110(1): 56-62.